1. Field of the Invention
This application claims the benefit of French Patent Application No. 10/01137, filed Mar. 23, 2010.
This invention relates to the field of implantable biomaterials known as bone cements and more specifically to the field of acrylic cements used for vertebroplasty and the sealing of prostheses.
It concerns a system for preparing a bone cement polymer comprising two components which react with each other when they are mixed to form a solid polymer material, one of which is provided in the form of a gel with high stability under normal storage conditions. Another aim of the invention is a composition intended for use in the preparation of such cement.
2. Description of the Related Art
Nowadays, bone cements are widely used in orthopedic surgery in the sealing of prostheses (hip, knee, shoulder), treatment of vertebral compression fractures, or as filling material for vertebroplasty. In particular, the techniques of vertebroplasty and kyphoplasty are used to restore vertebrae damaged by trauma or disease. It is thus possible to relieve back pain when analgesic treatments are ineffective.
These techniques are of great interest to patients because the pain relief rate is very high and fast. The literature reports a net decrease or disappearance of back pain in 80 to 90% of cases. There is also an obvious improvement in mobility and quality of life for patients treated within hours or days after surgery. In cases of vertebral bone tumors, vertebroplasty provides significant and rapid relief and allows patients to regain a standing position within 24 to 72 hours after surgery.
The technique of percutaneous vertebroplasty has been used for about 20 years and has become a growing success. It involves injecting cement based on polymethylmethacrylate (PMMA) into the vertebrae under fluoroscopic and/or tomographic control.
The majority of currently used cements are prepared from two-component systems that must be mixed just before its implementation to obtain an implantable material. The first component essentially consists of a prepolymer powder and the second component of a liquid monomer. The liquid monomer, typically methylmethacrylate (MMA) additionally contains a polymerization activator such as pyridylmethyltoluidine (DMTP), the role of which is to accelerate the chain reaction, and an inhibitor such as hydroquinone (HQ) which prevents spontaneous polymerization of the monomer. The prepolymer, typically consisting of poly(methylmethacrylate) (PMMA) is in the form of small spherical balls or beads. It contains in turn a polymerization initiator such as benzoyl peroxide (BPo). A radiopaque compound may be mixed with the powder to allow visualizing the cement during and after injection.
Upon the mixture of the two components, the initiator present in the powder phase reacts with the gas present in the liquid phase to create highly reactive chemical species (free radicals) that initiate the polymerization chain.
The mixture acquires a certain consistency, a given viscosity level, which differs depending on the cements and their preparation conditions and which will eventually evolve gradually to form a solid mass. For example, the sealing cements are, after mixing the powder and liquid components, either very watery (called “low viscosity”) or very pasty (called “high viscosity”). It is the same for cements used in vertebroplasty or kyphoplasty.
The viscosity of cement immediately after mixing is now controlled by the partial dissolution of beads present in the first prepolymer component by the monomer liquid of the second component. It then increases the average molecular weight of prepolymer chains involved in expanding the polymerization reaction, which induces a gradual increase in viscosity. The process and the kinetics of polymerization of acrylic cements used in orthopedic surgery are well known to those skilled in the craft, as are the mechanical properties of cements obtained.
We know in particular that the monomer and the prepolymer must be made in such proportions that the reaction is as complete as possible. Indeed, if the monomer is in excess, an undesirable release phenomenon will occur, while if it is of insufficient quantity the un-dissolved prepolymer balls will give the cement a grainy appearance and make it fragile. Thus, for a cement vertebroplasty, it is recommended to follow a prepolymer and monomer ratio of about 1.5; this ratio may go up to about 3 for the sealing of prosthesis.
In practice, the surgeon will, based on data provided in the instructions for use of cement, therapeutic indications and his personal opinion, judge when the consistency of cement has reached a satisfactory level in order to begin implementation with minimal risk to the patient. Depending on the type of cement, one of two situations will arise.
If the cement is a low viscosity cement, the surgeon must wait until polymerization progresses in order to begin the implementation of cement. This dead time, which may last up to 15 minutes, is time lost. The risks associated with the implantation of “low viscosity” acrylic cement originate in particular the risk of a too-fluid concrete passing into the circulatory system. Taking into account this risk requires the practitioner to make an accurate, though largely empirical, assessment of the viscosity level achieved.
If, however, the cement is a high viscosity cement, the surgeon may begin the implantation of the completed mixture, but must operate using sophisticated, and therefore expensive, injection systems,
In both cases, the viscosity of the mixture changes very quickly and the implementation must be conducted expeditiously once it has reached the desired level. The surgeon must operate in a very short period of time, usually several minutes, which is a significant additional burden for him and a risk to the patient.
To overcome these problems, using a low-viscosity type cement is proposed, one whose formulation is designed so that, immediately after mixing the components, the viscosity is at a level sufficient to begin its implementation. An adequately pasty consistency every time immediately after mixing would eliminate waiting time and reduce the risk of too-watery cement passing into the circulatory system, reducing uncertainty in addition to the subjective assessment of the practitioner. Similarly, a longer implementation time (over 10 minutes for example) would allow the surgeon to implant cements in a more controlled and mastered manner.
The solution proposed to address these requirements is based on the use of a two-component system, in which the second component is in the form of a viscous gel rather than in liquid form.
This gel is obtained by dissolving a certain amount of prepolymer beads in a liquid monomer. In doing so, the usual reagents are used, the first component including a polymerization initiator, and the second component including a polymerization reaction accelerator (activator) and a polymerization inhibitor. Consequently, the very low viscosity liquid phase containing the monomer of the current system with two components is replaced by a phase in the form of a gel that, after being mixed with the powder phase, gives the cement a higher viscosity level.
When mixing the second gel component with the first powder component, a cement paste is obtained, the consistency of which can be implemented without waiting time, which has the added advantage of a viscosity well calibrated to the initial time t0, and not subjectively assessed after a longer or shorter period.
In practice, however, it was found that the second component had a reduced stability that prevented permanent storage or imposed refrigerated storage. Indeed, despite the presence of hydroquinone in the inhibitory component gel, it was observed that polymerization occurs after a certain period of time. This problem is well known since there are currently marketed products in the form of gels, which are either made from acrylic monomers like Bis-GMA, Bis-EMA, TEGDMA or UDMA (e.g. Cortoss™ cement from Orthovita), or from MMA and PMMA [Shim et al., Biomaterials, 2005], and all these acrylic gels must be stored and transported under refrigerated conditions, failing which they are usable only for a very short time, about a few months. Knowing that cements currently used in orthopedics have 3-year expiration periods in normal ambient temperature conditions, we understand that hospitals do not want to be forced to organize the cold storage of such medical devices, which would impose significant logistical constraints.
However, to date, no alternative solution to maintaining the cold has been proposed to allow storage of products at room temperature without any premature polymerization occurring.